Diabetes mellitus is a common chronic disease, characterized by hyperglycemia. The onset of diabetes associates with insulin resistance in peripheral tissue, reduction of insulin in vivo and increase of gluconeogenesis in liver. When the disease cannot be controlled effectively through diet and exercise, insulin or oral hypoglycemic drugs for treatment are needed. At present, hypoglycemic drugs comprise biguanides, sulfonylureas, insulin sensitizers, glinides, α-glucosidase inhibitors and DPP-IV inhibitors, etc. However, these current hypoglycemic drugs have shortcomings. Biguanides can cause lactic acidosis. Sulfonylureas can result in severe hypoglycemia. Glinides can result in hypoglycemia if used improperly. Insulin sensitizers can lead to edema, heart failure and weight gain. α-Glucosidase inhibitors can cause abdominal bloating and diarrhea. DPP-IV inhibitors need to combine with metformin to achieve the desired effect of hypoglycemia. Therefore, there is an urgent need to develop novel, safer, and more effective hypoglycemic agents.
It has been found by research that glucose transporter proteins are a class of carrier proteins embedded in the cell membrane for transporting glucose. Glucose must be in virtue of glucose transporter protein to cross lipid bi-layer structure of cell membranes. Glucose transporter proteins are divided into two categories. The first category includes sodium-dependent glucose transporters (SGLTs), and the other category includes glucose transporters (GLUTs). Two major family members of SGLTs are SGLT-1 and SGLT-2. SGLT-1 is mainly distributed in small intestine, kidney, heart and windpipe, predominantly expressed in the intestinal brush border and the distal S3 segment of the renal proximal tubule, and a few expressed in heart and windpipe, and transports glucose and galactose with a sodium to glucose ratio of 2:1. While SGLT-2 is mainly distributed in kidney, predominantly expressed in the distal S1 segment of the renal proximal tubule, and transports glucose with a sodium to glucose ratio of 1:1. In biological bodies, glucose is transported by SGLTs through active transport against a concentration gradient with simultaneous energy consumption. While glucose is transported by GLUTs through facilitated diffusion along a concentration gradient without energy consumption in the transport process. Research indicates that normally plasma glucose is filtered in the kidney glomeruli in which 90% of glucose in the early S1 segment of the renal tubule is actively transported to epithelial cells by SGLT-2 and 10% of glucose in the distal S3 segment of the renal tubule is actively transported to epithelial cells by SGLT-1, and then transported to peripheral capillary network by GLUT of epithelial basement membrane accomplishing reabsorption of glucose by renal tubules. Hence, SGLTs is the first stage in regulation of glucose metabolism in cells, and an ideal target for treating diabetes effectively. It has been found by research that the patients with SGLT-2 impairment would excrete large amounts of urine glucose. This provides the factual basis of treating diabetes by reducing glucose uptake through inhibiting SGLT-2 activity. Therefore, inhibiting activity of SGLTs transport protein could block reabsorption of glucose in renal tubules and increase excretion of glucose in urine to normalize the plasma glucose concentration and further control the diabetes and diabetic complications. Inhibiting SGLTs would not influence the normal anti-regulatory mechanism of glucose, which may cause the risk of hypoglycemia. Meanwhile, lowering blood glucose through an increase of renal glucose excretion could promote weight loss in obese patients. It has also been found by research that the mechanism of action of SGLTs inhibitors is independent of pancreatic β cell dysfunction or the degree of insulin resistance. Therefore, the efficacy of SGLTs inhibitors will not decrease with the severe insulin resistance or β-cell failure. SGLTs inhibitors could be used alone or in combination with other hypoglycemic agents. Therefore, SGLTs inhibitors are ideal and novel hypoglycemic agents.
In addition, it has also been found by research that SGLTs inhibitors can be used for treating diabetes-related complications. Such as retinopathy, neuropathy, kidney disease, insulin resistance caused by glucose metabolic disorder, hyperinsulinemia, hyperlipidemia, obesity, and so on. Meanwhile, SGLTs inhibitors also be used in combination with current treatment regimens, such as sulphonamides, thiazolidinedione, metformin, and insulin, etc., which can reduce the dose without impacting on the effectiveness of the medicine, and thereby avoid or reduce side effects, and improve patient compliance. At present, the marketed SGLTs inhibitors comprise Canagliflozin and Dapagliflozin, etc., which are mainly used for treating diabetes type II and diabetes complications.
Chemical stability, solid state stability and “storage duration” of an active compound are particularly important factors in a drug preparation. For example, the compound is generally milled to a suitable size in order to ensure an even distribution of the active compound in a preparation process. In order to avoiding a decomposition of the active compound in the milling process, a high stability of the active compound is very important. Ideal drug substances and a composition thereof can be stored effectively during the evaluation period, and there are no obvious changes in physical and chemical properties (e.g., chemical composition, density, water absorbing rate, solubility and dissolution rate, etc.) of the active constituent. A known amorphous form drug substance cannot solve the above problems well. For instance, a drug substance in an amorphous form is difficult to be managed and prepared, its solubility is unreliable and the chemical and physical property of which is usually unstable.
The application of a drug complex shows a broad development prospect in the field of medical science, a crystalline form of a complex, also known as a cocrystal form, is gradually become a new selection for a solid form of the active compound in a drug preparation, the potential solid form of the compound is broadened, the formation of a cocrystal form can provide a better way to change the physical and chemical properties of an active ingredient, the specific expected properties are realized by forming a cocrystal form of an active ingredient and a cocrystallization agent (ligand). The exploration of a complex of the medicinal compound and a cocrystal form thereof provides more opportunities to improve the overall performance of the pharmaceutical product.